Effects of HMPA on the structure and aldol stereoselectivity of lithiated arylacetonitriles
by Wing-shiu Lo
xiv, 96 leaves : ill. ; 30 cm
HMPA is a favorite additive for optimizing reaction rates and selectivities of organolithium reagents. The first chapter of the thesis reviews published observations of the effects of HMPA on selected reaction outcomes, and on the structure of organolithium compounds....[ Read more ]
HMPA is a favorite additive for optimizing reaction rates and selectivities of organolithium reagents. The first chapter of the thesis reviews published observations of the effects of HMPA on selected reaction outcomes, and on the structure of organolithium compounds.
The second chapter describes a reinvestigation of Michael Lo's discovery that HMPA reverses the diastereoselectivity of selected nitrile aldol reactions. This reinvestigation included a determination of the scope of the HMPA-mediated syn-selective nitrile aldol reaction, and a study of other additives as HMPA replacements. The previous assumption that HMPA's effects were due to a change in kinetic selectivity was also reinvestigated by looking for evidence of retro-aldol reaction. We confirmed earlier conclusions by Kam Moon Lo and Carlier that in pure THF at -78 ℃, the aldol reaction is essentially irreversible over 30 minutes. However, HMPA was found to effectively promote retro-aldol reaction under these conditions. Thus the observed syn-selective addition of lithiated 1-naphthylacetonitrile to aromatic aldehydes in THF-HMPA solution is due to thermodynamic control.
Chapter 3 describes 7Li and 3lP NMR studies of lithiated phenyl- and l-napthylacetonitrile in pure THF and THF-HMPA solution. The main objective of these studies was to determine whether lithiated arylacetonitriles exist in pure THF as solvent-separated ion pairs, or as contact ion pairs in rapid chemical exchange. By examining 7Li NMR linewidths of these species in pure THF, and by monitoring the 7Li and 3lP NMR spectra as a function of added HMPA ("HMPA-titration"), it was concluded that these species exist in pure THF as monomeric contact ion pairs. These studies allowed characterization of mono-HMPA solvated dimers, mono- and bis-HMPA solvated monomers, and HMPA-solvated separated ion pairs. Thus, following Reich's terminology, lithiated arylacetonitriles can be classified as "HMPA-separable contact ion pairs". Experimental details for the original thesis work are described in Chapter 4.